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Low Levels of Tumor Necrosis Factor Increase Tumor Growth by Inducing an Endothelial Phenotype of Monocytes Recruited to the Tumor Site

¹ The Department of Veterans Affairs Medical Center and Departments of ² Pathology, ³ Internal Medicine, ⁴ Pediatrics, and ⁵ Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tenessee

Requests for reprints: Pampee P. Young, Vanderbilt University School of Medicine, Department of Pathology, 1161 21st Avenue South, C2217A MCN, Nashville, TN 37232. Phone: 615-936-1098; Fax: 615-343-7023; E-mail: pampee.young{at}vanderbilt.edu.

Key Words: endothelial • myeloid • TNF

Microenvironmental cues instruct infiltrating tumor-associated myeloid cells to drive malignant progression. A subpopulation of tumor-associated myeloid cells coexpressing endothelial and myeloid markers, although rare in peripheral blood, are primarily associated with tumors where they enhance tumor growth and angiogenesis. These biphenotypic vascular leukocytes result from the endothelial differentiation of myeloid progenitors, a process regulated by tumor necrosis factor (TNF) in vitro. An in vivo increase in tumor-derived TNF expression promoted tumor growth and vascularity of mouse melanoma, lung cancer, and mammary tumors. Notably, tumor growth was accompanied by a significant increase in myeloid/endothelial biphenotypic populations. TNF-associated tumor growth, vascularity, and generation of tumor vascular leukocytes in mouse melanoma tumors were dependent on intact host TNF receptors. Importantly, TNF-expressing tumors did not exhibit increased inflammation over control tumors, suggesting a unique action related to myeloid to endothelial differentiation. Our studies suggest that TNF constitutes a tumor microenvironment signal that biases recruited monocytes toward a proangiogenic/provasculogenic myeloid/endothelial phenotype. [Cancer Res 2009;69(1):338–48]